Method of treating memory disorders using R-enantiomers of N-propargyl-aminoindan compounds

ABSTRACT

R(+)-N-propargyl-1-aminoindan, its preparation and use and pharmaceutical compositions containing it. The novel compound was found to be useful for the treatment of human patients for Parkinson&#39;s disease, memory disorders, dementia of the Alzheimer type (DAT), depression and the hyperactive syndrome.

This is a divisional of U.S. Ser. No. 08/198,205 filed Feb. 17, 1994(now U.S. Pat. No. 5,457,133), which is a continuation of U.S. Ser. No.08/063,461, filed May 18, 1993, now abandoned, which is a continuationof U.S. Ser. No. 07/632,184, filed Dec. 21, 1990, now abandoned,claiming priority of Israeli Patent Application No. 92,952, filed Jan.3, 1990, the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention is in the field of selective irreversibleinhibitors of the enzyme monoamine oxidase (hereinafter MAO) and relatesto the R(+) enantiomer of N-propargyl-1-aminoindan (hereinafter, PAI)which is a selective irreversible inhibitor of the B-form of themonoamine oxidase enzyme (hereinafter, MAO-B). The invention alsorelates to pharmaceutical compositions containing R(+) PAI which isparticularly useful for the treatment of Parkinson's disease, memorydisorders and dementia of the Alzheimer type (DAT), depression, andhyperactive syndrome in children.

BACKGROUND OF THE INVENTION AND PRIOR ART

Parkinson's disease is widely considered to be the result of degradationof the pre-synaptic dopaminergic neurons in the brain, with a subsequentdecrease in the amount of the neurotransmitter dopamine, that is beingreleased. Inadequate dopamine release, therefore, leads to the onset ofvoluntary muscle control disturbances symptomatic of Parkinson'sdisease.

Various procedures for treating Parkinson's disease have beenestablished and are currently in widespread use, for example, theadministration of L-Dopa together with a decarboxylase inhibitor, suchas L-carbidopa or benzerazide. The decarboxylase inhibitor protects theL-Dopa molecule from peripheral decarboxylation and thus ensures L-Dopauptake by the remaining dopaminergic neurons in the striatum of thebrain. Here the L-Dopa is converted into dopamine resulting in increasedlevels of dopamine in these neurons. In response to physiologicalimpulses these neurons are therefore capable of releasing larger amountsof dopamine, the quantity of which approximates the normal requiredlevels. This treatment therefore alleviates the symptoms of the diseaseand contributes to the well-being of the patients.

However, this L-Dopa treatment has its drawbacks, the main one beingthat its effectiveness is optimal only in the first few years followingthe onset of treatment. After this initial period the clinical responseis diminished and is accompanied by adverse side effects which includedyskinesia, fluctuation in efficacy throughout the day ("on-off effect")and psychiatric symptoms such as confusional states, paranoia andhallucinations. This fall-off in the effect of L-Dopa treatment isattributed to a number of factors, including the natural progression ofthe disease, alteration in dopamine receptors as a consequence ofincreased dopamine production or increased levels of dopaminemetabolites, and pharmacokinetic problems of L-Dopa absorption (reviewedby Youdim et al., Progress in Medicinal Chemistry, Vol. 21, Chapter 4,pp. 138-167 (1984), Eds. Ellis and West, Elsevier, Amsterdam).

In order to overcome the drawbacks of the L-Dopa treatment, varioustreatments have been devised in which L-Dopa is combined with MAOinhibitors, with the aim of reducing the metabolic breakdown of thenewly formed dopamine (see for example, U.S. Pat. No. 4,826,875).

MAO exists in two forms known as MAO-A and MAO-B which have selectivityfor different substrates and inhibitors. For example, MAO-B metabolizesmore efficiently substrates such as 2-phenylethylamine and isselectively and irreversibly inhibited by (-)-deprenyl (as describedbelow).

It should be noted, however, that combining L-Dopa with an inhibitor ofboth MAO-A and MAO-B is undesirable leading to adverse side effectsrelated to an increased level of catecholamines throughout the neuraxis.Furthermore, complete inhibition of MAO is also undesirable as itpotentiates the action of sympathomimetic amines such as tyramineleading to the so-called "cheese effect" (reviewed by Youdim et al.,Handbook of Experimental Pharmacology, Vol. 90, Chap. 3 (1988) Eds,Trendelenburg and Weiner, Springer-Verlag). As MAO-B was shown to be thepredominant form of MAO in the brain, selective inhibitors for this formwere thus considered to be a possible way for achieving a decrease indopamine breakdown on the one hand, together with a minimization of thesystemic effects of total MAO inhibition, on the other.

One of these selective MAO-B inhibitors, (-)-deprenyl, has beenextensively studied and has been used as an MAO-B inhibitor to augmentL-Dopa treatment. This treatment with (-)-deprenyl is generallyfavorable, not causing the "cheese effect" at doses causing nearlycomplete inhibition of MAO-B (Elsworth et al., Physchopharmacology, 57,33 (1978). Furthermore, addition of (-)-deprenyl to a combination ofL-Dopa and decarboxylase inhibitor to Parkinson's patients leads toimprovements in akinesia and overall functional capacity as well as theelimination of "on-off" type fluctuations (reviewed by Birkmayer &Riederer in "Parkinson's Disease" pp. 138-149, Springer-Verlag (1983)).

Thus, (-)-deprenyl enhances and prolongs the effect of L-Dopa andpermits-a lowering of the dosage of L-Dopa whereby the adverse effectsof L-Dopa treatment are limited.

However, (-)-deprenyl is not without its own adverse sides effects whichinclude activation of pre-existing gastric ulcers and occasionalhypertensive episodes. Furthermore, (-)-deprenyl is an amphetaminederivative and is metabolized to yield amphetamine and methamphetamineswhich may lead to undesirable side effects associated with thesesubstances, e.g. increased heart rate (Simpson, BiochemicalPharmacology, 27, 1591 (1978); Finberg et al., in "Monoamine OxidaseInhibitors--The State of the Art", pp. 31-43, Eds. Youdim and Paykel,(1981) Wiley).

Other compounds that are selective irreversible inhibitors of MAO-B butwhich are free of the undesirable effects associated with (-)-deprenylhave been described. One such compound, namely N-propargyl-l-aminoindan.HCl (racemic-PAI.HCl) was described in GB 1,003,686, GB 1,037,014 andU.S. Pat. No. 3,513,244. It is a potent, selective, irreversibleinhibitor of MAO-B, is not metabolized to amphetamines and does not giverise to unwanted sympathomimetic effects.

In comparative animal tests racemic PAI was shown to have considerableadvantages over (-)-deprenyl, for example, racemic PAI produced nosignificant tachycardia, did not increase blood pressure (effectsproduced by doses of 5 mg/kg of (-)-deprenyl), and did not lead tocontraction of nictitating membrane nor to an increase in heart rate atdoses up to 5 mg/kg (effects caused by (-)-deprenyl at doses over 0. 5mg/kg). Furthermore, racemic PAI.HCl does not potentiate thecardiovascular effects of tyramine (Finberg et al. in "Enzymes andNeurotransmitters in Mental Disease", pp. 205-219, (1980), Eds. Usdin etal., Pub. John Wiley and Sons, N.Y.; Finberg et al. (1981) in "MonoamineOxidase Inhibitors--The State of the Art", ibid; Finberg and Youdim,British Journal Pharmacol. 85 451, (1985).

One object of this invention is to separate the racemic PAI compoundsand to produce an enantiomer with MAO-B inhibition activity.

Since deprenyl has a similar structure to PAI and it is known that the(-)-enantiomer of deprenyl, i.e. (-)-deprenyl, is considerably morepharmaceutically active than the (+)-enantiomer, it was expected, bythose skilled in the art, that only the (-) enantiomer of PAI would bethe active MAO-B inhibitor.

However, contrary to such expectations, upon resolution of theenantiomers, it was found, in accordance with the present invention thatthe (+)-PAI enantiomer was in fact the active MAO-B inhibitor while the(-)enantiomer showed extremely low MAO-B inhibitory activity.Furthermore, the (+)PAI enantiomer surprisingly also had a higher degreeof selectivity for MAO-B inhibition than the corresponding racemic formand may thus have less undesirable side effects in the treatment of theindicated disease. These findings are based on both in vitro and in vivoexperiments as presented hereinafter in greater detail.

It was subsequently shown that (+)-PAI has the R absolute configuration.This was also surprising based on the expected structural analogy withdeprenyl and the amphetamines.

The high degree of stereoselectivity of pharmacological activity betweenR(+)-PAI and the S(-) enantiomer is also remarkable. The compoundsR(+)-PAI is nearly four orders of magnitude more active than the S(-)enantiomer in MAO-B inhibition. This ratio is significantly higher thanthat observed between the two deprenyl enantiomers (Knoll and Magyar,Adv. Biochem. Physchopharmacol., 5, 393 (1972); Magyar, et al., ActaPhysiol. Acad. Sci. Hung., 32, 377 (1967). Furthermore, in somephysiological tests, (+) deprenyl was reported to have equal or evenhigher activity than the (-) enantiomer (Tekes, et al., Pol. J.Pharmacol. Pharm. 40, 653 (1988).

N-methyl-N-propargylaminoindan (MPAI) is a more potent inhibitor of MAOactivity, but with lower selectivity for MAO-B over A (Tipton, et al.,Biochem. Pharmacol., 31, 1250 (1982)). Surprisingly, in this case wehave found only small degree of difference in the relative activities ofthe two resolved enantiomers thus further emphasising the remarkablenessof the case of R(+)-PAI. (See Table 1A).

Another object of the present invention is to provide for the first timeuse of the pharmaceutically active PAI-enantiomer alone (without L-Dopa)for treatment of Parkinson's disease, dementia and depression (seereview by Youdim et al. in Handbook of Experimental Pharmacology, Vol.90/I, (1988), chap.3, Eds. Trendelenberg and Wiener).

It is yet another object of the invention to provide for the use of thepharmaceutically active PAI-enantiomer for pre-treatment alone ortogether with synergistic agents, of Parkinson's disease in order todelay the L-Dopa treatment and its associated adverse side effects. Thisapproach has been studied with respect to (-)-deprenyl which was shownto be effective when administered alone to early Parkinsonism patients,and may also have a synergistic effect in these patients whenadministered together with α-tocopherol (a vitamin E derivative), (TheParkinson's Study Group, New England J. Med., 321(20), 1364-1371,(1989)).

In addition to its usefulness in treating Parkinson's disease,(-)-deprenyl has also been shown to be useful in the treatment ofpatients with dementia of the Alzheimer type (DAT) (Tariot et al.,Psychopharmacology, 91, 489-495, 1987), and in the treatment ofdepression (Mendelewicz and Youdim, Brit. J. Psychiat. 142, 508-511,1983). Thus, the R(+)-PAI compound of this invention has been shown topossess activity in restoration of memory, thus having potential fortreatment of memory disorders, dementia and especially useful inAlzheimer's disease and for the treatment of the hyperactive syndrome inchildren.

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus provides as a novel compound theR(+)-enantiomer of N-propargyl-1-aminoindan [R(+)PAI] of the formula(I): ##STR1## and pharmaceutically acceptable acid addition saltsthereof. The present invention also relates to the preparation ofR(+)PAI, to pharmaceutical compositions comprising the compound R(+)PAItogether with suitable carriers and to the use of R(+)PAI for thetreatment of human patients for Parkinson's disease, memory disorders,dementia of the Alzheimer type and hyperactive syndrome.

The R(+)PAI may be obtained by optical resolution of racemic mixtures ofR and S-enantiomer of PAI. Such a resolution can be accomplished by anyconventional resolution method, well known to a person skilled in theart, such as those described in "Enantiomers, Racemates and Resolutions"by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, N.Y.,1981. For example, the resolution may be carried out by preparativechomatography on a chiral column. Another example of a suitableresolution method is the formation of diastereomeric salts with a chiralacid such as tartaric, malic, mandelic acid or N-acetyl derivatives ofaminoacids, such as N-acetyl leucine, followed by recrystallisation toisolate the diastereomeric salt of the desired R enantiomer.

The racemic mixture of R and S enantiomers of PAI may be prepared, e.g.as described in GB 1,003,676 and GB 1,037,014. The racemic mixture ofPAI can also be prepared by reacting 1-chloroindan or 1-bromoindan withpropargylamine. Alternatively, this racemate may be prepared by reactingpropargylamine with 1-indanone to form the corresponding imine, followedby reduction of the carbon-nitrogen double bond of the imine with asuitable agent, such as sodium borohydride.

In accordance with this invention, the R enantiomer of PAI, can also beprepared directly from the optically active R-enantiomer of 1-aminoindanby reaction with propargyl bromide or propargyl chloride, in thepresence of an organic or inorganic base and optionally in the presenceof a suitable solvent.

Suitable organic or inorganic bases for use in the above reaction are,e.g., triethylamine, pyridine, alkali metal carbonates or bicarbonatesetc. If the reaction is conducted in the presence of a solvent, this maybe chosen from, e.g., toluene, methylene chloride and acetonitrile. Apreferred method of preparation of the aforementioned compound is thereaction between R-1-aminoindan with propargyl chloride using potassiumbicarbonate as a base and acetonitrile as solvent.

The above described reaction of 1-aminoindan generally results in amixture of unreacted primary amine, the desired secondary amine and thetertiary amine N,N-bispropargylamino product. The desired secondaryamine, i.e. N-propagyl-1-aminoindan, can be separated from this mixtureby any conventional separation method, such as chromatography,distillation, selective extraction, etc.

The R-1-aminoindan starting material can be prepared by methods knownfrom the literature, for example Lawson and Rao, Bichochemistry (1980)19, 2133 and the references cited therein, and European Patent No.235,590.

The R-1-aminoindan can also be prepared by resolution of a racemicmixture of the R and S enantiomers, e.g. by formation of diastereomericsalts with chiral acids, or by any other known method, such as thosereported in the above mentioned "Enantiomers, Racemates and Resolutions"by J. Jacques et al, Pub. John Wiley & Sons, N.Y., 1981. Alternatively,the R-1-aminoindan starting material may be prepared by reacting1-indanone with an optically active amine, followed by reduction of thecarbon-nitrogen double bond of the resulting imine by hydrogenation overa suitable catalyst, such as palladium on carbon, platinum oxide,Raney-nickel etc. Suitable optically active amines are, for example, oneof the antipodes of phenethylamine or an ester of an aminoacid, such asvaline or phenylalanine. The benzylic N-C bond may be cleavedsubsequently, by hydrogenation under non-vigorous conditions.

Additional methods for preparing R-1-aminoindan are the hydrogenation,as described above, of indan-1-one oxime ethers, wherein the alkylportion of the ether contains an optically pure chiral center.Alternatively, a non-chiral derivative of indan-1-one containing acarbon-nitrogen double bond, such as an imine or oxime, can be reducedwith a chiral reducing agent, e.g. a complex of lithiumaluminium-hydride and ephedrine.

For the preparation of pharmaceutically acceptable acid addition saltsof the compound of R(+)PAI, the free base can be reacted with thedesired acids in the presence of a suitable solvent by conventionalmethods. Similarily, an acid addition salt may be converted to the freebase form in a known manner.

In accordance with the present invention, the compound R(+)PAI may beprepared as pharmaceutical compositions particularly useful for thetreatment of Parkinson's disease, dementia of the Alzheimer type (DAT)or depression. Such compositions may comprise the compound of R(+)PAI orpharmaceutically acceptable acid addition salts thereof, together withpharmaceutically acceptable carriers and/or excipients. For example,these compositions may be prepared as medicaments to be administeredorally, parenterally, rectally or transdermally. Suitable forms for oraladministration include tablets, compressed or coated pills, dragees,sachets, hard or soft gelatin capsules, sub-lingual tablets, syrups andsuspensions; for parenteral administration the invention providesampoules or vials that include an aqueous or non-aqueous solution oremulsion; for rectal administration there are provided suppositorieswith hydrophilic or hydrophobic vehicles; and for topical application asointments and transdermal delivery there are provided suitable deliverysystems as known in the art.

These above compositions may be used alone to treat Parkinson's disease,Alzheimer's disease or depression, or alternatively, in the case ofParkinson's disease, they may be used as an adjunct to the conventionalL-Dopa treatments. A pharmaceutical composition for oral use in the formof tablets or capsules may comprise R(+)-N-propargyl-1-aminoindan,Levodopa, and a decarboxylase inhibitor. A composition may comprise 2-20mg of R(+)-N-propargyl-1-aminoindan, 50-250 mg of Levodopa, and 10-25 mgof L-Carbidopa. A composition may comprise 2-10 mg ofR(+)-N-propargyl-1-aminoindan, 50-200 mg of Levodopa, and 12.5-50 mg ofbenserazide.

The preferred dosages of the active ingredient, i.e., R-PAI compounds,in the above compositions are within the following ranges: for oral orsuppository formulations 2-20 mg per dosage unit to be taken daily andmore preferably 5-10 mg per dosage unit to be taken daily may be used;and for injectable formulations 1-10 mg/ml per dosage unit to be takendaily and more preferably 2-5 mg/ml per dosage unit to be taken dailymay be used.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic representation of the results according to Example19.

FIG. 2 is a graphic representation of the results according to Example19.

FIG. 3A is a graphic representation of the results according to Example19.

FIG. 3B: see description of FIG. 3A

FIG. 4 is a graphic representation of the results according to Example20.

FIG. 5 is a graphic representation of the results according to Example20.

FIG. 6 is a graphic representation of the results according to Example20.

FIG. 7 is a graphic representation of the results according to Example20.

FIG. 8 is a graphic representation of the results according to Example20.

FIG. 9 is a graphic representation of the results according to Example20.

FIG. 10 is a graphic representation of the results according to Example20.

FIG. 11 is a graphic representation of the results according to Example20.

FIG. 12 is a graphic representation of the results according to Example21.

FIG. 13 is a graphic representation of the results according to Example21.

FIG. 14 is a graphic representation of the results according to Example21.

FIG. 15 is a graphic representation of the results according to Example21.

FIG. 16 is a graphic representation of the results according to Example22.

The invention will now be described in more detail in the followingnon-limiting examples and their accompanying Tables and Figures.

EXAMPLE 1 Racemic N-propargyl-1-aminoindan hydrochloride

Racemic 1-aminoindan (10.0 g ) and 10.4 g of potassium carbonate wereadded to 75 ml of acetonitrile. The resulting suspension was heated to60° C. and 4.5 g of propargyl chloride were added dropwise.

The mixture was stirred at 60° C. for 16 hours, whereafter most of thevolatiles were removed by distillation in vacuo. The residue waspartitioned between 10% aqueous sodium hydroxide and methylene chloride.

The organic phase was dried and the solvent removed by distillation. Theresidue was flash chromatographed on silica gel, eluting with 40% ethylacetate/60% hexane. The fractions containing the title compound as afree base were combined and the eluant replaced by ether. The etherealsolution was treated with gaseous HCl, the precipitate formed wasisolated by suction filtration and recrystallized from isopropanol toyield 7.3 g of the title compound, m.p. 182°-4° C.

Chromatographic and spectroscopic data were in accordance with theliterature (U.S. Pat. No. 3,513,244) and an authentic sample.

NMR (δ, CDCl₃): 2.45 (2H, m), 2.60 (1H, t), 2.90 (1H, m), 3.45 (1H, m),3.70 (2H, d), 4.95 (1H, t), 7.5 (4H, m) ppm.

EXAMPLE 2 S-(-)-N-Propargyl-1-aminoindan hydrochloride

The title compound in free base form was isolated by resolving theracemic mixture of the free base of Example 1 on a Chiracel OJ(cellulose tris[p-methylbenzoate]) preparative HPLC column eluting with10% isopropanol/90% hexane and collecting the first eluted major peak.The resulting oil was converted to the title compound (hydrochloride) bytreatment of a 10% diethyl ether solution of the oil with gaseous HCland the resulting precipitate was collected by suction filtration.

[α]_(D) -29.2° (1%, ethanol), m.p. 182°-184° C. Other chromatographicand spectroscopic properties were identical with the hydrochloride saltof Example 1.

EXAMPLE 3 R-(+)-N-Propargyl-1-aminoindan hydrochloride

The title compound was prepared as in Example 2 above, except that thesecond eluted peak from the preparative HPLC was collected; [α]_(D)+29.1° (0.8%, ethanol), m.p. 179°-181° C. Other chromatographic andspectroscopic properties were identical with the hydrochloride salt ofExample 1.

EXAMPLE 4 R-(+)-N-propargyl-1-aminoindan hydrochloride

R-(-)-1-aminoindan (12.4 g) and 12.9 g of potassium carbonate were addedto 95 ml of acetonitrile. The resulting suspension was heated to 60° and5.6 g of propargyl chloride were added dropwise. The mixture was stirredat 60° C. for 16 hours, whereafter most of the volatiles were removed bydistillation in vacuo. The residue was partitioned between 10% aqueoussodium hydroxide and methylene chloride.

The organic phase was dried and the solvent removed in vacuo, theresidue was flash chromatographed on silica gel eluting with 40% ethylacetate/60% hexane. Fractions containing the free base of the titlecompound were combined and the solvent replaced by ether. The etherealsolution was treated with gaseous HCl and the resulting precipitate wasisolated by suction filtration and recrystallized from isopropanol toyield 6.8 g of the title compound, m.p. 183°-185° C., [α]_(D) +30.90(2%, ethanol). Spectral properties were identical to those reported forthe compound of Example 1.

EXAMPLE 5 S-(-)-N-propargyl-1-aminoindan hydrochloride

The title compound was prepared by the method of Example 4, except thatS-(+)-1-aminoindan was used as starting material. The product exhibited[α]_(D) -30.3 (2%, ethanol ), m.p. 183°-5° C. Spectral properties wereidentical to those reported for the compound of Example 1.

EXAMPLE 6 Di (R-(+)-N-propargyl-1-aminoindan)L-tartarate

To a solution of L-Tartaric acid (4.4 g ) in 48 ml of boiling methanolwas added a solution of R-(+)-N-propargyl-1-aminoindan free base (5.0 g)in methanol (48 ml ). The solution was heated to reflux and 284 ml oft-butylmethyl ether was added over 20 minutes. The mixture was heatedfor an additional 30 minutes, cooled, and the resulting precipitate wasisolated by suction filtration to yield 6.7 g of the title compound,m.p. 175°-177° C. [α]_(D) (1.5, H₂ O)=+34.3; Anal. calcd. for C₂₈ H₃₂ O₆N₂ ; C, 68.26, H, 6.56, N, 5.69. Found: C., 68.76; H, 6.57; N, 5.61.

EXAMPLE 7 R-(+)-N-Methyl-N-propargyl-1-aminoindan hydrochloride

The free base form of R-(+)-N-propargyl-1-aminoindan from Example 4 (1.2grams), potassium carbonate (0.97 grams) and methyl iodide (1 gram) wereadded to 15 ml of acetone and the resulting suspension heated to refluxunder a nitrogen atmosphere for 8 hrs. Thereafter the volatiles wereremoved under reduced pressure and the residue partitioned between 10%aqueous sodium hydroxide (30 ml) and methylene chloride (30 ml). Theorganic phase was dried and the solvent removed in vacuo. The residuewas flash chromatographed on silica gel eluting with 40% ethylacetate/60% hexane. Fractions containing the title compound as a freebase were combined and the solvent replaced by diethyl ether. Theethereal solution was treated with gaseous HCl, the volatiles removed invacuo and the residue recrystallized from isopropanol to yield 400 mg ofthe title compound as a white crystalline solid, m.p.: 134°-136° C.[α]_(D) +31.40 (ethanol). NMR(δCDCl₃):2.55 (2H, m); 2.7 (1H, br.s); 2.8(3H, s); 3.0 (1H, m); 3.4 (1H, m); 3.9 (2H, br.s): 5.05 (1H, m) 7.7 (4H,m) ppm.

EXAMPLE 8 S-(-)-N-methyl-propargyl-1-aminoindan hydrochloride

The title compound was prepared as in Example 7 above, except thatS-(-)-N-propargyl-1-aminoindan (free base) from Example 5 was used asstarting material. All of the physical and spectral properties of thetitle compound were identical to those in Example 7 except for the[α]_(D) -34.9° (ethanol).

EXAMPLE 9

    ______________________________________                                        Tablet Composition                                                            ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               5.0    mg                                         Pregelatinized starch       47.0   mg                                         Lactose hydrous             66.0   mg                                         Microcrystalline cellulose  20.0   mg                                         Sodium starch glycolate     3.0    mg                                         Talc                        1.5    mg                                         Magnesium stearate          0.7    mg                                         ______________________________________                                    

Purified water added as required for granulation.

EXAMPLE 10

    ______________________________________                                        Tablet Composition                                                            ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               1.0    mg                                         Lactose hydrous             50.0   mg                                         Pregelatinized starch       36.0   mg                                         Microcrystalline cellulose  14.0   mg                                         Sodium starch glycolate     2.2    mg                                         Talc                        1.0    mg                                         Magnesium stearate          0.5    mg                                         ______________________________________                                    

Purified water added as required for granulation.

EXAMPLE 11

    ______________________________________                                        Capsule Composition                                                           ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               5.0    mg                                         Pregelatinized starch       10.0   mg                                         Starch                      44.0   mg                                         Microcrystalline cellulose  25.0   mg                                         Ethylcellulose              1.0    mg                                         Talc                        1.5    mg                                         ______________________________________                                    

Purified water added as required for granulation.

EXAMPLE 12

    ______________________________________                                        Injection Composition                                                         ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               5.0    mg                                         Dextrose anhydrous          44.0   mg                                         ______________________________________                                    

HCl added to pH 5

Purified water added as required for 1 ml

EXAMPLE 13

    ______________________________________                                        Injection Composition                                                         ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               1.0    mg                                         Sodium chloride             8.9    mg                                         ______________________________________                                    

HCl added to pH 5

Purified water added as required to 1 ml

EXAMPLE 14

    ______________________________________                                        Injection Composition                                                         ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               2.0    mg                                         Sodium chloride             8.9    mg                                         ______________________________________                                    

HCl added to pH 5

Purified water added as required to 1 ml

EXAMPLE 15

    ______________________________________                                        Syrup Composition                                                             ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                             5.0     mg                                          Sucrose                   2250.0  mg                                          Saccharin sodium          5.0     mg                                          Methylparaben             6.0     mg                                          Propylparaben             1.0     mg                                          Flavor                    20.0    mg                                          Glycerin USP              500     mg                                          Alcohol 95% USP           200     mg                                          ______________________________________                                    

Purified water as required to 5.0 ml

EXAMPLE 16

    ______________________________________                                        Sublingual Tablets                                                            ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               2.5    mg                                         Microcrystalline cellulose  20.0   mg                                         Lactose hydrous             5.0    mg                                         Pregelatinized starch       3.0    mg                                         Povidone                    0.3    mg                                         Coloring agent              q.s.                                              Flavor                      q.s.                                              Sweetener                   q.s.                                              Talc                        0.3    mg                                         ______________________________________                                    

Blend the excipients and the active and granulate with an ethanolsolution of Povidone. After drying and weighing, it is blended with thetalc and compressed.

EXAMPLE 17

    ______________________________________                                        PAI Sublingual Tablets                                                        ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               5.0    mg                                         Microcrystalline cellulose  15.0   mg                                         Pregelatinized starch       12.0   mg                                         Ethyl cellulose             0.3    mg                                         Talc                        0.3    mg                                         ______________________________________                                    

Purified water added as required for granulation.

EXAMPLE 18

    ______________________________________                                        Tablet Composition                                                            ______________________________________                                        R(+)-N-propargyl-1-aminoindan hydrochloride                                                               5.0    mg                                         Levodopa                    100.0  mg                                         Carbidopa                   25.0   mg                                         Pregelatinized starch       24.0   mg                                         Starch                      40.0   mg                                         Microcrystalline cellulose  49.5   mg                                         Col. D & C Yellow No. 10    0.5    mg                                         Col. D & C Yellow No. 6     0.02   mg                                         ______________________________________                                    

Alcohol USP added as required for granulation.

The following Examples and their accompanying Tables and Figures relateto the Biological Experiments carried out in accordance with thisinvention.

EXAMPLE 19

Inhibition of MAO activity in vitro

Experimental protocol

The MAO enzyme source was a homogenate of rat brain in 0.3M sucrose,which was centrifuged at 600 g for 15 min. The supernatant was dilutedappropriately in 0.05M phosphate buffer, and pre-incubated with serialdilutions of compounds of general formula I: R(+)-PAI, S(-)-PAI andracemic-PAI (wherein A is hydrogen) for 20 min at 37° C. ¹⁴ C-labelledsubstrates (2-phenylethylamine, hereinafter PEA; 5-hydroxytryptamine,hereinafter 5-HT) were then added, and the incubation continued for afurther 20 min (PEA), or 30-45 min (5-HT). Substrate concentrations usedwere 50 uM (PEA), and 1 mM (5-HT). In the case of PEA, enzymeconcentration was chosen so that not more than 10% of the substrate wasmetabolized during the course of the reaction. The reaction was thenstopped by addition of tranylcypromine (to final concentration 1 mM),and the incubate filtered over a small column of Amberlite CG-50,buffered to pH 6.3. The column was washed with 1.5 ml water, the eluatespooled and the radioactive content determined by liquid scintillationspectrometry. Since the amine substrates are totally retained on thecolumn, radioactivity in the eluate indicates the production of neutraland acidic metabolites formed as a result of MAO activity. Activity ofMAO in the sample was expressed as a percentage of control activity inthe absence of inhibitors, after subtraction of appropriate blankvalues. The activity determined using PEA as substrate is referred to asMAO-B, and that determined using 5-HT as MAO-A.

Results:

Inhibitory activity of the R(+)-PAl, S(-)-PAI and racemic-PAI compoundsof formula I were examined separately in vitro, and the results oftypical experimental runs are shown in FIGS. 1 and 2. The entireexperiment was repeated three times. Concentration of inhibitorproducing 50% inhibition of substrate metabolism (IC-50) was calculatedfrom the inhibition curves, and is shown in Table 1. From this data itcan be seen that:

(a) the R(+)-PAI is twice as active as the racemate for inhibition ofMAO-B;

(b) the R(+)-PAI is 29 times more active for inhibition of MAO-B thanMAO-A;

(c) the S(-)-PAI is only 1/6,800 as active as the R(+)-PAI forinhibition of MAO-B, and shows little or no selectivity between MAO-Band MAO-A.

                  TABLE 1                                                         ______________________________________                                        IC-50 (nM) VALUES FOR INHIBITION OF MAO-A AND                                 MAO-B BY RACEMIC-PAI AND THE R(+) AND S(-)                                    ENANTIOMERS THEREOF IN RAT BRAIN                                              HOMOGENATE IN VITRO                                                           IC-50 (nM)                                                                    Com-  MAO-A            MAO-B                                                  pound:                                                                              S(-)PAI R(+)PAI   Rac  S(-)PAI                                                                              R(+)PAI Rac                               ______________________________________                                              26000   73        140  17000  2.5     5                                 ______________________________________                                    

The results of the same experiment using R(+) and S(-) MPAI(N-methyl-N-propargyl-1-aminoindan) are reported in Table 1A. Each ofthe enantiomers of MPAI is less selective between MAO-B and MAO-Ainhibition than R(+)PAI. Furthermore, R(+)MPAI is only five times asactive as S(-)MPAI in MAO-B inhibition, in contrast to R(+)PAI which isabout 7000 times as active as S(-)PAI in this assay.

                  TABLE 1A                                                        ______________________________________                                        IC-50 (nM) VALUES FOR INHIBITION OF MAO-A AND                                 MAO-B BY THE R(+) AND S(-) ENANTIOMERS OF                                     MPAI IN RAT BRAIN HOMOGENATE IN VITRO                                         IC-50 (nM)                                                                    MAO-A                MAO-B                                                    Compound:                                                                             S(-)MPAI  R(+)MPAI   S(-)MPAI                                                                              R(+)MPAI                                 ______________________________________                                                70        3          50      10                                       ______________________________________                                    

Some experiments were also carried out with human cerebral corticaltissues, obtained 6 hours post-mortem, and treated as described above.The results of such an experiment are shown in FIG. 3 (where theR(+)PAI, S(-)PAI and racemic PAI compounds were those equivalent toformula I).

EXAMPLE 20

Inhibition of MAO activity in vivo: acute treatment

Experimental protocol:

Rats (male Sprague-Dawley derived) weighing 250±20 g were treated withone of the enantiomers or the racemic form of PAI by intraperitonealinjection (ip) or oral gavage (po) and decapitated 1 h or 2 h laterrespectively. Groups of three rats were used for each dose level ofinhibitor, and MAO activity determined in brain and liver using thegeneral technique described above. The amount of protein in eachincubation was determined using the Folin-Lowry method, and enzymeactivity calculated as nmol substrate metabolized per hour incubationfor each mg protein. Activity of MAO in tissues from animals treatedwith inhibitors was expressed as a percentage of the enzyme activity ina group of control animals, administered vehicle (water for oraladministration; 0.9% saline for ip injection) and killed as above.

Results:

None of the dose levels used with the inhibitor drugs produced anyobvious behavioural alteration. The results are depicted in FIGS. 4 to11. Following ip administration, compound R(+)-PAI produced 90%inhibition of brain MAO-B activity at a dose of 0.5 mg/kg. The same doseproduced only 20% inhibition of MAO-A activity. By oral administration,the same dose of R(+)-PAI produced 80% inhibition of MAO-B with nodetectable inhibition of MAO-A. Essentially similar results were seenfor inhibition of hepatic MAO, as for brain MAO. The doses producing 50%inhibition of MAO-A and MAO-B (IC-50) were calculated from theinhibition curves, and are shown in Table 2. These data show:

(a) that MAO inhibitory activity of compound R(+)-PAI is maintained invivo in the rat;

(b) that selectivity for inhibition of MAO-B, as opposed to MAO-A, byR(+)-PAI is maintained in vivo;

(c) that the much greater activity of the (+)-as opposed to(-)-enantiomer, is maintained in vivo;

(d) that the compounds are effectively absorbed after oraladministration; and

(e) that the compounds effectively pass the blood-brain barrier, andeffectively inhibit brain MAO. The fact that R(+)-PAI was about twice asactive as the racemic compound for inhibition of MAO-B is a reflectionof the extremely low activity of S(-)-PAI for inhibition of MAO-B.

                  TABLE 2                                                         ______________________________________                                        IC-50 VALUES (mg/kg) FOR INHIBITION OF MAO-A                                  AND MAO-B BY R(+)-PAI, S(-)-PAI OR RACEMIC-                                   PAI, IN THE RAT FOLLOWING INTRAPERITONEAL                                     (IP) INJECTION OR ORAL ADMINISTRATION (PO)                                    IC-50 (mg/kg)                                                                 Com-  MAO-A            MAO-B                                                  pound:                                                                              S(-)PAI R(+)PAI   Rac  S(-)PAI                                                                              R(+)PAI Rac                               ______________________________________                                        IP    >10     1.2       2.5  >10    0.07    0.22                              BRAIN                                                                         IP    >10     5         5    >10    0.06    0.11                              LIVER                                                                         PO    >10     >5        >5   >10    0.17    0.29                              BRAIN                                                                         PO    >10     >5        >5   >10    0.05    0.09                              LIVER                                                                         ______________________________________                                    

EXAMPLE 21

Inhibition of MAO activity in vivo: chronic treatment

Experimental protocol:

Rats (specification as in Example 20:4 animals for each dose level) weretreated with compound R(+)-PAI or racemic form at three dose levels(0.05, 0.1 and 0.5 mg/kg) by oral administration, one dose daily for 21days, and decapitated 2 hours after the last dose. The activity of MAOtypes A and B was determined in brain and liver as described in Example20.

Results:

A dose of 0.1 mg/kg daily of compound R(+)-PAI produced a good degree ofselective inhibition, with more than 80% inhibition of brain MAO-B and20% or less inhibition of brain MAO-A. At the higher dose of 0.5 mg/kgdaily, MAO-A was still inhibited by less than 50% (FIGS. 12 and 13).Hepatic MAO showed a similar degree of selective inhibition (FIGS. 14and 15). Compound R(+)-PAI was again more potent than the racemic formof the inhibitor, by a factor of about twofold. In the case of brainMAO, R(+)-PAI had a better degree of selectivity for inhibition of MAO-Bthan the racemic form.

These results show that selectivity of MAO-B inhibition can bemaintained following chronic treatment with the compounds. As with otherirreversible inhibitors, the degree of enzyme inhibition is greater withchronic treatments than following a single dose of the drug. CompoundR(+)-PAI shows a better degree of selectivity for inhibition of brainMAO-B than the racemic compound.

EXAMPLE 22

Irreversible nature of MAO inhibition

Experimental protocol:

A single dose of compound R(+)-PAI (1 mg/kg) was administered by ipinjection to groups of 4 rats, and the animals killed 2,6,18,24,48 and72 hours later. Activity of MAO-B was determined in whole brain tissuesas described herein before.

Results:

The results are shown in FIG. 16. Maximal inhibition of MAO-B wasattained at 6 hours after the injection. MAO activity had only returnedto 30% control activity at 72 hours after the injection. This experimentdemonstrates the irreversible nature of the MAO inhibition by compoundR(+)-PAI.

EXAMPLE 23

Potentiation of tyramine pressor effect in conscious rats

Experimental protocol:

Rats were anesthetised with a mixture of pentobarbital (30 mg/kg) andchloral hydrate (120 mg/kg) by intraperitoneal injection. The leftcarotid artery and jugular vein were cannulated with fine polythenetubing (artery) or fine silicone rubber tubing connected to polyethylenetubing (vein), the distal end of which was brought under the skin to ananchor point behind the neck. The tubing was filled with heparinisedsaline solution, and plugged with a fine steel rod. The animals weretreated with 20 mg chloramphenicol by intramuscular injection andallowed to recover from the operation overnight. The following day, therats were placed in a high-walled container permitting free movement.The arterial catheter was connected to a pressure transducer via a 100cm length of saline-filled, fine-bore polyethylene tubing, and thevenous catheter connected to a 1 ml syringe via a similar length oftubing, which, together with the syringe, contained a solution oftyramine hydrochloride in saline (1 mg/ml).

Following an equilibration period of 30 to 40 min, tyramine injections(50 or 100 g) were given, and blood pressure responses recorded. Atleast 15 min was maintained between injections, after return of bloodpressure to control values. Control pressor responses were established,and then one of the drugs injected intra-peritoneally, and tyramineresponses repeated over the next 4 hours. Area under the blood pressureresponse curve was estimated, and the ratio of this area after treatmentto before treatment determined, using the average off 3 to 4 valuesobtained in control period, and 1 to 3 hours after injection of thecompounds.

Results:

The results are shown in Table 3. Compound R(+)-PAI at a dose of 1mg/kg, (which causes complete inhibition of MAO-B in brain and liver,and 40 to 50% inhibition of MAO-A in these tissues) caused nosignificant potentiation of tyramine pressor response. At the higherR(+)-PAI dose of 5 mg/kg, (which causes more extensive inhibition ofMAO-A in brain and periphery), there was a significant potentiation ofthe tyramine pressor response, which was similar in extent to thatproduced by the same dose of deprenyl, and less than that produced byclorgyline (at a dose which inhibits hepatic MAO-A activity by over85%).

                  TABLE 3                                                         ______________________________________                                        POTENTIATION OF TYRAMINE PRESSOR EFFECT IN                                    CONSCIOUS RATS BY MAO INHIBITORS                                                                No. of  Ratio Area Under                                             Dose     rats    Pressor Response                                    Inhibitor                                                                              (mg/kg)  (n)     Curve; After/Before                                                                        SEM                                    ______________________________________                                        Saline            12      1.25         0.28                                   Clorgyline                                                                             2        6       10.39        2.13                                   (-)Deprenyl                                                                            1        2       1.15                                                (-)Deprenyl                                                                            5        3       2.36         0.16                                   R(+)PAI  1        3       1.38         0.7                                    R(+)PAI  5        3       3.49         0.98                                   ______________________________________                                    

From this experiment it can be concluded that compound R(+)-PAI causesno potentiation of the tyramine pressor effect at a dose whicheffectively inhibits MAO-B.

EXAMPLE 24

Suppression of MPTP-Induced dopaminergic Toxicity by R(+)-PAI

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin thatdamages nigrostriatal dopaminergic neurons in several mammalian speciesincluding mice and produces a parkinsonian syndrome in humans andprimates. A crucial initial step in the mechanism of its neurotoxicityinvolves conversion of MPTP to its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+). This reaction is catalyzed by the enzyme MAO-Band probably takes place outside of dopaminergic neurons, mainly inglia. It is known that MPTP is both a substrate and an irreversibleinhibitor of MAO-B. Pretreatment of experimental animals with MAO-Binhibitors such as deprenyl or pargyline protects against and preventsthe MPTP-induced damage to nigrostriatal neurons because the oxidativeconversion of MPTP to MPP+ is blocked. One of the major currenthypotheses suggests that the progressive nigrostriatal degeneration inParkinson's may be due to exposure to environmentally-derived exogenousMPTP-like neurotoxins. In such case, there is an additional strongindication to initiation of sustained treatment with an MAO-B inhibitorfrom the very early stages of Parkinson's disease in the hope that itwill neutralize the damaging effects of such yet putative MPTP-liketoxins and thus arrest or slow down the progression of the illness. Asuccessful MAO-B inhibitor drug is currently judged by its ability toblock MPTP-induced damage to nigrostriatal dopaminergic neurons in vivo.We therefore tested the (-) and (+) enantiomers of PAI for their potencyin preventing or attenuating the MPTP-induced striatal dopaminedepletions in mice.

Experimental Protocol:

Male C57 black mice (20-25 g weight) were injected with MPTP.HCl (30mg/kg dissolved in distilled water, s.c.) or vehicle alone or one hourafter pretreatment with the (-) or (+) isomers of PAI (2.5 mg/kg, i.p.)or with deprenyl (5 mg/kg, i.p.) and decapitated 5 days later. Brainswere removed and corpora striata dissected on an ice-cold glass plateand frozen on dry ice. Striatal tissues were homogenized in 0.1Mperchloric acid, and deproteinized aliquots containingdihydroxybenzylamine as an internal standard were assayed for dopamineand its major metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC) usingHPLC with electro-chemical detection.

Results:

Table 4 shows the results of this experiment. Treatment with MPTP aloneproduced marked striatal dopamine (DA) and DOPAC depletions. Treatmentwith the (-) and (+) enantiomers of PAI or with (-) deprenyl did notaffect striatal DA concentrations. Pretreatment with the (-) isomer ofPAI did not affect the MPTP-induced DA and DOPAC levels in striatum. The(+)-isomer of PAI given before MPTP, completely abolished the reductionin striatal DA and DOPAC levels produced by the toxin. At a dose of 2.5mg/kg it was equipotent to (-) deprenyl (5 mg/kg) in its protectiveeffect.

                  TABLE 4                                                         ______________________________________                                        EFFECT OF PRETREATMENT WITH THE (-) AND (+)                                   ENANTIOMERS OF THE MAO-B INHIBITOR PAI ON                                     THE STRIATAL DA AND DOPAC DEPLETIONS                                          INDUCED BY MPTP IN MICE IN VIVO.                                                              DA       DOPAC                                                                (ng/mg protein)                                               ______________________________________                                        Control           162.8 ± 7.2                                                                           8.4 ± 0.5                                     MPTP               53.1 ± 6.2                                                                           3.2 ± 0.3                                     (-)-PAI           174.0 ± 4.8                                                                           7.5 ± 0.2                                     (-)-PAI + MPTP     53.4 ± 6.9                                                                           7.0 ± 0.6                                     (+)-PAI           185.0 ± 6.9                                                                           3.3 ± 0.3                                     (+)-PAI + MPTP     177.8 ± 14.4                                                                         6.0 ± 0.3                                     (-) Deprenyl      170.6 ± 7.1                                                                           5.6 ± 0.3                                     (-) Deprenyl + MPTP                                                                             197.0 ± 8.0                                                                           6.4 ± 0.5                                     ______________________________________                                         Above values for DA and DOPAC expressed as Mean ± S.E.M., and No. of       rats, n = 7-11 in each group.                                            

These results indicate that the R(+)-PAI is an excellent MAO-B inhibitorin vivo, and is of especially great potential for the treatment ofParkinson's disease.

While the invention has been described with reference to theaforementioned Examples and their accompanying Tables and Figures, it isnot restricted thereto. Various modifications and applications of theinvention are possible, for example, compounds of Formula I may becombined, in a synergistic way, with α-tocopherol (Vit. E. deriv.) forthe treatment of Parkinson's disease.

EXAMPLE 25

Effect of PAI enantiomers on amphetamine induced stereotype behavior insenescent rats

Amphetamine is known to induce stereotypic behaviour (Sulser, F. &Sanders-Bush, E. Ann. Rev. Pharmacol. 11: 209-230 (1971)) by themobilization of endogenous dopamine. Amphetamine is not metabolized byMAO-B. Inhibition of MAO-B by an effective inhibitor and administrationof amphetamine cause release of dopamine which will not undergodegradation by the inhibited MAO-B. Thus, an increase of synapticdopamine is expected after administration of amphetamine and effectiveMAO-B inhibitor leading to an increase in stereotypebehavior--potentiation of the amphetamine effect. The extent of thisbehaviour is rated in accordance with the number of lateral headmovements over a period of 1 minute.

Experimental Protocol:

The test compound was administered at a dose of 0.5 mg/kg/day indrinking water, 24 hours before the infliction of hypoxia (92%nitrogen+8% oxygen for 6 hours). Following that, amphetamine wasinjected s.c. at a dose of 0.5 mg/kg 45 min. later, lateral headmovements were counted.

Results:

The results of these experiments are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        EFFECT OF PAI ISOMERS ON AMPHETAMINE-                                         INDUCED STEREOTYPE BEHAVIOUR IN SENESCENT                                     RATS (CONTROL AND HYPOXIALESIONED)                                                                     Stereotype                                           Group          Treatment Behavior Rating                                      ______________________________________                                        Control (6)    --        87 ± 10                                           Control (5)    (+) PAI   126 ± 16-                                         Control (4)    (-) PAI   94 ± 18                                           Hypoxia lesioned (5)                                                                         --        93 ± 12                                           Hypoxia lesioned (6)                                                                         (+) PAI   143 ± 6-                                          ______________________________________                                         Numbers in parenthesis are numbers of animals tested P < 0.001 with           respect to untreated hypoxia group or untreated control group                 correspondingly                                                          

The results in Table 5 indicate that (+)PAI caused significantpotentiation of the amphetamine-induced stereotype behavior in bothhypoxia-lesioned and control rats. (-)PAI was totally inactive in thisrespect. These behavioral in vivo results corroborate previousbiochemical findings that (+)PAI is an active inhibitor of MAO-B in thebrain while (-)PAI is inactive in this respect.

EXAMPLE 26

Effect on R(+)PAI on the improvement or restoration of memory

Newborn rat pups subjected to a brief episode of anoxia and then allowedto resume their growth in a normal way, develop a long-lastingimpairment of memory (Speiser, et al., Behav. Brain Res. 30:89-94,1988). This memory impairment is expressed as an inferior performance inthe passive avoidance test.

The effect of R(+)PAI and S(-1)PAI on the improvement or restoration ofmemory was investigated in the passive avoidance test. If the drug iseffective it increases the latency of response to enter a darkcompartment or chamber where an electroshock has been experiencedearlier by the rat being tested. The latency of the maximal response is300 seconds.

Experimental Protocol:

Young rats were subjected to post-natal anoxia as described in Example27. R(+)PAI or S(-)PAI were administered according to one of thefollowing protocols:

Protocol A--Nursing mothers were given a dose of either isomer of 1-1.5mg/kg/day, in drinking water until weaning at 21 days. Following thatthe weaned offsprings were directly dosed with the same dose for 20days. Treatment was terminated at 40 days and the test was performed at60 days, that is 20 days after the last dose of the drug.

Protocol B--The dose was reduced to 0.5 mg/kg/day administered to thenursing mother till weaning at 21 days than directly to the young ratsto 60 days at which time the test was performed.

Passive Avoidance Test--The apparatus consisted of a lit chamberadjoining a dark chamber and a sliding door separating the two. Attraining, a rat was placed in the lit chamber for 30 sec. then the doorwas opened. The rat moved to the dark chamber with a latency that wasrecorded. Upon entry of the rat into the dark compartment, the door wasclosed and a 0.3 mA foot--shock was delivered for 3 sec.

Retention (memory) after 48 hours was determined by repeating the testand recording the latency to step through from light to darkness to anarbitrary maximum of 300 sec.

Results:

The results of these experiments are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                        EFFECT OF PAI ISOMERS ON PASSIVE AVOIDANCE                                    RESPONSE IN YOUNG RATS (60-DAYS OLD)                                                              Before     After                                          Group     Treatment Electroshock                                                                             Electroshock                                   ______________________________________                                        PROTOCOL A                                                                    Control   --        49 ± 13 201 ± 111                                   Control   (+)PAI    49 ± 19 220 ± 100(+9%)*                             Control   (-)PAI    48 ± 13 192 ± 116                                   Anoxia-lesioned                                                                         --        45 ± 11 183 ± 109                                   Anoxia-lesioned                                                                         (+)PAI    49 ± 10 239 ± 99(+19*)*                             Anoxia-lesioned                                                                         (-)PAI    55 ± 27 179 ± 123                                   PROTOCOL B                                                                    Control   --        53 ± 20 104 ± 101                                   Control   (+)PAI    48 ± 11 128 ± 119(+23%)*                            Anoxia-lesioned                                                                         --        45 ± 8  119 ± 105                                   Anoxia-lesioned                                                                         (+)PAI    52 ± 12 137 ± 126(+15%)*                            Anoxia-lesioned                                                                         (-)PAI    48 ± 19 112 ± 112                                   ______________________________________                                         -- Figures represent the latency in seconds for entering a dark               compartment where an electroshock had been first experienced by the rat       tested.                                                                       *The indicated percent increases are with respect to the anoxia or contro     groups correspondingly.                                                  

The experimental results indicated that (+)PAI but not (-)PAI iseffective in improving the memory of anoxia-lesioned and control rats.Drugs active in this test are considered to be potentially useful fortreatment of various memory impairment disorders, dementia andespecially senile dementia of the Alzheimer's type.

EXAMPLE 27

Effect of R(+)PAI on the anoxia-induced hyperactive syndrome in juvenilerats

Rats that had been exposed postnatally to anoxia and then left to growunder normal conditions show increased motor activity in the open fieldat the age of 10-42 days (Hertshkowitz et al., Dev. Brain Res. 7:145-155(1983)).

The effect of R(+)PAI and R(-)PAI on such hyperactive syndrome wasinvestigated.

Experimental Protocol:

Anoxia was performed on rat pups on the first post-natal day. They wereplaced in a glass chamber and exposed to 100% nitrogen for 25 min. Theywere resuscitated by intermittent massage softly applied to the chestand then returned to their respective mothers. Control rats received thesame treatment but with air instead of nitrogen.

The R(+)PAI or S(-)PAI (0.5 mg/kg/day ) was administered to the nursingmothers in drinking water, thereby transferred to the sucklings throughmilk.

Locomotion was measured in 6 fully computerized cages (28×28 cm) byrecording the number of crossing over a given period of time. Crossingsof grid infrared beams at 4-cm intervals initiated electrical impulseswhich fed a counter. Recordings of motor activity were made at the agesof 15 and 20 days, over a period of 15 min.

Results:

The experimental results are given in Table 7.

                  TABLE 7                                                         ______________________________________                                        EFFECT OF EACH OF THE TWO ENANTIOMERS ON                                      THE ANOXIA-INDUCED HYPERACTIVE SYNDROME                                                           15-day old  20-day old                                    Group     Treatment rats        rats                                          ______________________________________                                        Control   --        414 ± 192(11)                                                                          808 ± 212(12)                              Control   (+)PAI    254 ± 149(11)c                                                                         719 ± 110(13)                              Anoxia-lesioned                                                                         --        482 ± 119 (7)                                                                          858 ± 96 (9)                               Anoxia-lesioned                                                                         (+)PAI    276 ± 186(15)a                                                                         737 ± 150(16)c                             Anoxia-lesioned                                                                         (-)PAI    334 ± 196 (5)                                                                          778 ± 232 (6)                              ______________________________________                                         Numbers in parenthesis are numbers of animals tested.                         -- The figures are the number of crossings of infrared beam grid in the       activity cage over a period of 15 minutes.                                    a P < 0.001 compared to anoxia untreated group.                               b P < 0.05 compared to anoxia untreated group.                                c P < 0.05 compared to control group.                                    

These results indicate that chronic oral treatment with R(+)PAI at doseof 0.5 mg/kg administered to the nursing mother and reaching themilk-fed offspring, significantly improved the hyperactive syndrome.Consequently, R(+)PAI is a potentially useful drug for the treatment ofthe hyperactive syndrome in children.

We claim:
 1. A method of treating a subject for memory disorders whichcomprises administering to the subject an amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof effective to treat the subject.
 2. The method of claim 1,wherein the R(+)-N-propargyl-1-aminoindan or pharmaceutically acceptablesalt thereof is administered orally or rectally.
 3. The method of claim2, wherein the amount administered is 2 to 20 mg per daily dosage unit.4. The method of claim 3, wherein the amount administered is 5 to 10 mgper daily dosage unit.
 5. The method of claim 1, wherein theR(+)-N-propargyl-1-aminoindan or pharmaceutically acceptable saltthereof is administered parenterally.
 6. The method of claim 5, whereinthe amount administered is 1 to 10 mg per mL per daily dosage unit. 7.The method of claim 6, wherein the amount administered is 2 to 5 mg permL per daily dosage unit.